Structure–Activity Relationships of the Competence
Stimulating Peptide in <i>Streptococcus mutans</i> Reveal
Motifs Critical for Membrane Protease SepM Recognition and ComD Receptor
Activation
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Abstract
<i>Streptococcus
mutans</i> (<i>S. mutans</i>) is a Gram-positive
human pathogen that is one of the major contributors to dental caries,
a condition with an economic cost of over $100 billion per year in
the United States. <i>S. mutans</i> secretes a 21-amino-acid
peptide termed the competence stimulating peptide (21-CSP) to assess
its population density in a process termed quorum sensing (QS) and
to initiate a variety of phenotypes such as biofilm formation and
bacteriocin production. 21-CSP is processed by a membrane bound protease
SepM into active 18-CSP, which then binds to the ComD receptor. This
study seeks to determine the molecular mechanism that ties 21-CSP:SepM
recognition and 18-CSP:ComD receptor binding and to identify QS modulators
with distinct activity profiles. To this end, we conducted systematic
replacement of the amino acid residues in both 21-CSP and 18-CSP and
assessed the ability of the mutated analogs to modulate QS. We identified
residues that are important to SepM recognition and ComD receptor
binding. Our results shed light on the <i>S. mutans</i> competence QS pathway at the molecular level. Moreover, our structural
insights of the CSP signal can be used to design QS-based anti-infective
therapeutics against <i>S. mutans</i>